chr16-2093886-C-CG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001009944.3(PKD1):c.10745dupC(p.Val3584ArgfsTer43) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000702 in 1,424,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 frameshift
NM_001009944.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.53
Publications
1 publications found
Genes affected
PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-2093886-C-CG is Pathogenic according to our data. Variant chr16-2093886-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 521541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PKD1 | NM_001009944.3 | MANE Select | c.10745dupC | p.Val3584ArgfsTer43 | frameshift | Exon 36 of 46 | NP_001009944.3 | P98161-1 | |
| PKD1 | NM_000296.4 | c.10742dupC | p.Val3583ArgfsTer43 | frameshift | Exon 36 of 46 | NP_000287.4 | |||
| PKD1-AS1 | NR_135175.1 | n.304-829dupG | intron | N/A |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PKD1 | ENST00000262304.9 | TSL:1 MANE Select | c.10745dupC | p.Val3584ArgfsTer43 | frameshift | Exon 36 of 46 | ENSP00000262304.4 | P98161-1 | |
| PKD1 | ENST00000423118.5 | TSL:1 | c.10742dupC | p.Val3583ArgfsTer43 | frameshift | Exon 36 of 46 | ENSP00000399501.1 | P98161-3 | |
| PKD1 | ENST00000472659.1 | TSL:3 | n.182dupC | non_coding_transcript_exon | Exon 2 of 4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD2 exomes AF: 0.00 AC: 0AN: 195468 AF XY: 0.00
GnomAD2 exomes
AF:
AC:
0
AN:
195468
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 7.02e-7 AC: 1AN: 1424618Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1AN XY: 706968 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1424618
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
706968
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
32750
American (AMR)
AF:
AC:
0
AN:
41446
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25692
East Asian (EAS)
AF:
AC:
0
AN:
38046
South Asian (SAS)
AF:
AC:
0
AN:
82762
European-Finnish (FIN)
AF:
AC:
1
AN:
39932
Middle Eastern (MID)
AF:
AC:
0
AN:
5736
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1099042
Other (OTH)
AF:
AC:
0
AN:
59212
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
6
-
-
Polycystic kidney disease, adult type (6)
2
-
-
not provided (2)
1
-
-
Inborn genetic diseases (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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